RESEARCH PROJECT: PROJECT SUMMARY Kidney stone disease affects nearly 10% of the US population and adds $5 billion in financial burden to the US healthcare system annually. Great strides have been made in the physical removal of urinary stones, yet little progress has been made in treating or preventing stone pathogenesis. Patient stone and urine samples are routinely sent for chemical analysis, yet these data often have little impact on clinical decision making. Techniques for stone analysis have not advanced in many years and are often rudimentary, unreliable, and unreproducible. In addition, traditional 24-hour urine testing does not strongly predict future stone events and thus has limited utility in preventing stone recurrence. The most common (~85%) type of kidney stones are calcium-based, typically composed of calcium oxalate and/or calcium phosphate. Monitoring urinary calcium can be useful, but does not provide a complete indication of risk. Moreover, modifying calcium intake to change systemic calcium homeostasis does not have a significant impact on stone formation. New biomarkers of kidney stone disease are needed to improve pathophysyiological insight and the clinical management of kidney stone disease. Our previous Developmental Center for Interdisciplinary Research in Benign Urology work has shown that metals other than calcium, including zinc and strontium, play important roles in nephrolithiasis in an invertebrate model of stone formation. For example, increasing dietary zinc strongly promotes stone formation, while chelating zinc or inhibiting zinc transport dramatically reduces the amount of stones. To translate these findings to human kidney stone disease, this proposal to renew funding for our Center is focused on confirming the importance of trace metals in stone formation in a cohort of patients and demonstrating the value of comprehensive metallomic and targeted metabolomics analysis for predicting symptomatic stone episodes. We will follow a group of patients with calcium-based stones associated with hyperuricosuria and/or hypocitraturia in our urinary stone clinic at the University of California San Francisco. Stone and urine samples will be collected and tested with extensive metallomic and metabolomic analysis at our Analytic Core Facility. Combining the profiles from both metallomics and metabolomics of human stones and urine will allow us to create new diagnostic and therapeutic algorithms to augment or replace the relatively ineffective testing method currently in practice. Our goal is to identify the compositional patterns of metal and metabolite biomarkers to reveal new aspects of urinary stone pathophysiology. This work will culminate in a novel resource that will be made available to the urology community and will provide the necessary scientific platform to launch a large intervention study in patients with recurrent kidney stone disease.